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首页> 外文期刊>Biochemistry >Molecular dynamics simulations of class C beta-lactamase from Citrobacter freundii: Insights into the base catalyst for acylation
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Molecular dynamics simulations of class C beta-lactamase from Citrobacter freundii: Insights into the base catalyst for acylation

机译：弗氏柠檬酸杆菌C类β-内酰胺酶的分子动力学模拟：对酰化基础催化剂的认识

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摘要

Herein, we present results from molecular dynamics (MD) simulations of the class C beta-lactamase from Citrobacter freundii and its Michaelis complex with aztreonam. Four different configurations of the active site were modeled in aqueous solution, and their relative stability was estimated by means of quantum mechanical energy calculations. For the free enzyme, the energetically most stable configurations present a neutral Lys(67) residue or an anionic Tyr(150) side chain. Our calculations predict that these two configurations are quite close in terms of free energy, the anionic Tyr(150) state being favored by similar to 1 kcal/mol. In contrast, for the noncovalent complex formed between the C freundii enzyme and aztreonam, the energetic analyses predict that the configuration with the neutral Lys(67) residue is much more stable than the anionic Tyr(150) one (similar to 20 kcal/mol). Moreover, the MD simulations reveal that the neutral Lys(67) state results in a proper enzyme-aztreonam orientation for nucleophilic attack and in a very stable contact between the nucleophilic hydroxyl group of Ser(64) and the neutral amino side chain of Lys(67). Thus, both the computed free energies and the structural analyses support the assignation of Lys(67) as the base catalyst for the acylation step in the native form of the C freundii enzyme.
机译：在本文中，我们介绍了来自弗氏柠檬酸杆菌及其Michaelz与氨曲南的C类β-内酰胺酶的分子动力学（MD）模拟结果。在水溶液中对活性位点的四种不同构型进行了建模，并通过量子机械能计算估算了它们的相对稳定性。对于游离酶，在能量上最稳定的构型呈现中性的Lys（67）残基或阴离子Tyr（150）侧链。我们的计算预测，这两种构型在自由能方面非常接近，阴离子Tyr（150）态的相似性为1 kcal / mol。相比之下，对于C freundii酶和氨曲南之间形成的非共价复合物，能量分析表明，带有中性Lys（67）残基的构型比阴离子Tyr（150）构型要稳定得多（约20 kcal / mol ）。此外，MD模拟显示中性Lys（67）状态导致亲核攻击具有适当的酶-氨曲南取向，并且Ser（64）的亲核羟基与Lys（中性氨基侧链）之间的接触非常稳定。 67）。因此，计算出的自由能和结构分析均支持将Lys（67）指定为天然形式的Cfreundii酶酰化步骤的基础催化剂。

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